Departments of 1Medical Oncology and 2Gastrointestinal Surgery, Affiliated Hospital of Guangdong Medical University, Zhanjiang, China.
Gut Liver. 2022 Nov 15;16(6):861-874. doi: 10.5009/gnl210354. Epub 2022 Jun 10.
BACKGROUND/AIMS: The increased mortality of gastric cancer (GC) is mainly attributed to the development of chemoresistance. Circular RNAs, as the novel type of biomarkers in GC, have attracted wide attention. The purpose of this study was to investigate the functional role of circ_0081143 in GC with doxorubicin (DR) resistance and its potential action mechanism.
The expression of circ_0081143, miR-129-2-3p and YES proto-oncogene 1 (YES1) in GC tissues and cells was measured by quantitative real-time polymerase chain reaction. The half maximal inhibitory concentration value was calculated based on the MTT cell viability assay. Cell proliferation and apoptosis were monitored by MTT and flow cytometry assays. Transwell assays were employed to check cell migration and invasion. The protein levels of YES1 and apoptosis-related proteins were detected by western blotting. The interaction between miR-129-2-3p and circ_0081143 or YES1 was verified by dual-luciferase reporter and pull-down assays. A tumorigenicity assay was conducted to verify the role of circ_0081143 in vivo.
Circ_0081143 was highly expressed in DR-resistant GC tumor tissues and cells. Depletion of circ_0081143 reduced DR resistance and inhibited DR-resistant GC cell proliferation, migration and invasion. Circ_0081143 targeted miR-129-2-3p and inhibited the role of miR-129-2-3p. In addition, YES1 was a target of miR-129-2-3p, and its function was suppressed by miR-129-2-3p. Importantly, circ_0081143 positively modulated the expression of YES1 through mediating miR-129-2-3p. Circ_0081143 knockdown weakened the DR-resistant GC tumor growth in vivo.
Circ_0081143 knockdown weakened DR resistance and blocked the development of DR-resistant GC by regulating the miR-129-2-3p/YES1 axis. Our data suggest that circ_0081143 is a promising target for the treatment of GC with DR resistance.
背景/目的：胃癌（GC）死亡率的增加主要归因于化疗耐药的发展。环状 RNA 作为 GC 新型生物标志物，引起了广泛关注。本研究旨在探讨 circ_0081143 在 GC 与多柔比星（DR）耐药中的功能作用及其潜在作用机制。
采用实时定量聚合酶链反应检测 GC 组织和细胞中 circ_0081143、miR-129-2-3p 和 YES 原癌基因 1（YES1）的表达。根据 MTT 细胞活力测定计算半最大抑制浓度值。MTT 和流式细胞术检测细胞增殖和凋亡。Transwell 检测细胞迁移和侵袭。Western blot 检测 YES1 蛋白和凋亡相关蛋白水平。采用双荧光素酶报告和下拉实验验证 miR-129-2-3p 与 circ_0081143 或 YES1 的相互作用。进行肿瘤发生性实验验证 circ_0081143 在体内的作用。
circ_0081143 在 DR 耐药 GC 肿瘤组织和细胞中高表达。circ_0081143 耗竭降低了 DR 耐药性，并抑制了 DR 耐药性 GC 细胞的增殖、迁移和侵袭。circ_0081143 靶向 miR-129-2-3p 并抑制其作用。此外，YES1 是 miR-129-2-3p 的靶基因，其功能被 miR-129-2-3p 抑制。重要的是，circ_0081143 通过介导 miR-129-2-3p 正向调节 YES1 的表达。circ_0081143 耗竭减弱了体内 DR 耐药性 GC 肿瘤的生长。
circ_0081143 耗竭通过调节 miR-129-2-3p/YES1 轴减弱 DR 耐药性并阻止 DR 耐药性 GC 的发展。我们的数据表明，circ_0081143 是治疗 DR 耐药性 GC 的有前途的靶点。
